CN1022324C - Anhydrous crystal sodium salt of 5-chloro-3-(2-thenoyl)-2-oxyindole-1-carboxamide - Google Patents
Anhydrous crystal sodium salt of 5-chloro-3-(2-thenoyl)-2-oxyindole-1-carboxamide Download PDFInfo
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- CN1022324C CN1022324C CN88100555A CN88100555A CN1022324C CN 1022324 C CN1022324 C CN 1022324C CN 88100555 A CN88100555 A CN 88100555A CN 88100555 A CN88100555 A CN 88100555A CN 1022324 C CN1022324 C CN 1022324C
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- Prior art keywords
- thenoyl
- chloro
- oxyindole
- sodium salt
- anhydrous
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide having advantageous properties for formulation as an analgesic or antiinflammatory agent.
Description
The objective of the invention is to a kind of anhydrous, crystal type 5-chloro-3-(2-thenoyl that anodyne or antiphlogistic drug formula of medicine are had the novelty of favorable properties)-sodium salt of 2-oxyindole-1-methane amide.
Kadin, United States Patent (USP) 4,556, the above-mentioned 5-chloro-3-(2-thenoyl of the chemical formula shown in disclosing for No. 672 below having)-2-oxyindole-1-methane amide.
(the maybe salt that can be used for medicinal purpose) is as a kind of particularly preferred compound as pain relieving or antiphlogistic drug.The sodium salt of the formula I compound in the patent documentation disclosed herein is separated with semihydrate or hydrate.Further drying just makes monohydrate become anhydrous compound.We have determined that now formed several hydrates all are the mixture with variform (for example unbodied and acicular crystallization) usually.These different hydrate types have flowability and the static behaviour that causes the prescription difficulty usually.We also determined heat up and/or decompression under be unbodied and moisture absorption by the anhydrous product of preliminarily dried gained.Therefore wish to find a kind of these difficult crystal type sodium salts that overcomes very much.
We have found a kind of 5-chloro-3-(2-thenoyl of anhydrous, crystal type now)-sodium salt of 2-oxyindole-1-methane amide, it has valuable and not conspicuous character.Therefore this salt is easy to handle and be deployed into dosage form such as capsule.It is non-hygroscopic even reach at 90% o'clock in relative humidity and still keep stable dosage form.It dissolves sooner than the salt of hydration when it is pressed into tablet.
According to above-cited, this paper as the reference data, previously by the disclosed patent of Kadin, normally this favourable crystal salt is mixed with and as a kind of anodyne.
Be when room temperature, can prepare compound of the present invention simply unexpectedly by the sodium salt that is stirred in the hydrate type in the acetonitrile.Having observed this transformation does not have to carry out in the presence of other solvents when room temperature, but can also carry out at leisure in the toluene that refluxes.
In case find that the present invention is easy to carry out.The sodium salt of the compound of formula I preferably at first comes out with its isolated in form of hydrate in this method, stirs simply in acetonitrile then to obtain useful, anhydrous, nonhygroscopic crystal type sodium salt of the present invention.The temperature of this transformation is not critical in acetonitrile, but is easy to carry out when room temperature, removes heating or freezing required energy cost from.This on the other hand transformation can be carried out in toluene under the situation of reflux temperature with dean stark trap (Dean-Stark trap) azeotropic water removing of toluene, but and is not easy to carry out.Because lower boiling benzo is not really effective in this method, what produce usually is unbodied anhydrous product, can think that therefore higher temperature is critical for the formation of anhydrous crystal when the solvent of application except that acetonitrile.
Crystal salt of the present invention it is characterized in that it as the specific physical character shown in hereinafter.Above quoting previous common preparation and the application of disclosed this salt by Kadin.Hereinafter for example understand a kind of distinctive, stable and in the clinical useful capsule prescription that comprises salt of the present invention.
Following Example is to be used to the present invention is described and can not to be interpreted as limitation of the present invention, in this scope and its spirit many variations can be arranged.
Preparation method 1
5-chloro-3-(2-thenoyl)-sodium-salt hydrate of 2-oxyindole-1-methane amide
According to Kadin, United States Patent (USP) 4,556, the hydrate of No. 672 example 10 preparation titles.Use another kind of method, with 5-chloro-3-(2-thenoyl)-2-oxyindole-1-methane amide (example 8 of above-mentioned Kadin; 51.2g, 0.16mol) be suspended in the 400ml acetonitrile at 40 ℃, simultaneously with sodium bicarbonate (14.1g., 0.168mol) be dissolved in the 200ml water and heat to 40 ℃.The aqueous solution that this is warm is added in this warm acetonitrile suspension in 20 minutes, has small amount of foam to occur during this period.Stir resulting solution at 40 ℃, use the 5g decolorizing with activated carbon, stirred 30 minutes and filtered the acetonitrile of using 50ml again: water (1: 1) washing at 25 ℃.The filtrate that merges is concentrated by steam bath under vacuum with washing lotion,, be cooled to 25 ℃ and pass through first product of filtered and recycled when replacing acetonitrile with 200ml water when final volume is about 500ml.With this solid of 50ml water washing.The mother liquor that merges and washing lotion gas carried to 400ml generate second batch of product, after the drying, the heavy 35.76g(of firstling moisture 6.4% under air) and second crowd of heavy 16.77g(of product moisture 6.2%) be 90% through the gauged output of water content.The water content of calculating monohydrate is 5.0%, demonstrates 4 endotherms (about 110,150,237 and 255) with these two batches of products of determine with dsc method.
Example 1
The 5-chloro-3-(2-thenoyl of anhydrous, crystal type)-sodium salt of 2-oxyindole-1-methane amide.
5-chloro-3-(2-thenoyl with hydration)-sodium salt of 2-oxyindole-1-methane amide (52.5g is according to the another kind of method preparation of preparation method 1) stirs under room temperature in the acetonitrile of 52.5ml, reclaims title product after filtration, with the washing of 50ml acetonitrile; And obtain 46.7g(95% in 55 ℃ of dryings in a vacuum) title product; Xln under polarization microscope; In 50-300 ℃ scope, use determine with dsc method, be presented at 255 ± 2 ℃ and locate an independent endotherm clearly.
Analytical calculation C
14H
8ClN
2O
3SNa:
C，49.06;H，2.35;N，8.18;S，9.35;Cl，10.34;
Sulfated ash, 20.72; H
2O, O; At 100 ℃ of drying loss in vacuum, O.
Measured value
C，48.85;H，2.39;N，8.22;S，9.54;Cl，10.43;
Sulfated ash, 20.58; H
2O, 0.07; In 100 ℃ of drying loss in vacuum, 0.07.
Form tangible contrast with the hydrate type, the hydrate type is orange, and present anhydrous sodium salt is yellow.
The title compound of the sample (preparation method 1) of hydrate type and current anhydrous type is broken into fine particle and, is at diameter with 2000 pounds end pressure
J＜1,2〉inch mould in be pressed into small pieces.During each compressing tablet, stamping machine is removed and covered the bottom of pressing mold, so that the dissolution rate test is carried out in the monoplane of known surf zone with paraffin.The mould that will contain the pressurized medicine is put into a dissolving drag that has blade by American Pharmacopeia, make blade be in the tablet exposed surface on the 2.5cm place, at water with at 0.5M borate buffer solution (pH9.0) among both, with regard to inner dissolution rate (this is an important factor to the drug effect of oral dosage form), fast about three times of anhydrous type than hydrate.
Anhydrous type demonstrates the slight tendency that becomes hydrate.Even at the wet granulation of the applied water of following capsular preferred preparation on, also can not form hydrate (not obtaining proof) by not becoming orange color change by yellow
Example 2
Contain anhydrous 5-chloro-3-(2-thenoyl)-the oral capsule dosage type of 2-oxyindole-1-methane amide sodium salt
With following composition mix,, be dried to Karl Fischer at last and contain moisture 5% with the wet granulation of 875ml water;
5-chloro-3-(2-thenoyl)-2-oxyindole-1-first
Acid amides 600.00g
（561.52g.A
＊）
Microcrystalline Cellulose
（Avicel PH101） 885.75g.
The W-Gum 236.25g. of hydration
Povidone（PVC-30） 105.00g.
(* A is meant the activity equivalent of free acid)
That to do then, wet particle pulvis further with following composition mix,
Sodium starch glycollate
（Explotab） 210.00g.
Magnesium Stearate 42.00g.
Sodium lauryl sulphate 21.00g.
The mixture of the making preparation of using filling weight and be 375mg on a normally used capsule filling machine contains the soft gel capsule of 100mg.A.When to the dog oral administration medicine supplying,, demonstrate 89% high bioavailability by blood levels, so this class capsule shows extremely good bioavailability with the comparison of offeing medicine with oral liquid.
Claims (1)
1, a kind of method of sodium salt of 5-chloro-3-(2-the thenoyl)-2-oxyindole-1-methane amide for preparing anhydrous, crystal type is characterized in that the hydrate of corresponding this compound is stirred with acetonitrile.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| USPCT/US87/000201 | 1987-02-02 | ||
| USPCT/US87/00201 | 1987-02-02 | ||
| PCT/US1987/000201 WO1988005656A1 (en) | 1987-02-02 | 1987-02-02 | Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN88100555A CN88100555A (en) | 1988-08-17 |
| CN1022324C true CN1022324C (en) | 1993-10-06 |
Family
ID=22202263
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN88100555A Expired - Fee Related CN1022324C (en) | 1987-02-02 | 1988-02-02 | Anhydrous crystal sodium salt of 5-chloro-3-(2-thenoyl)-2-oxyindole-1-carboxamide |
Country Status (42)
| Country | Link |
|---|---|
| US (1) | US5036099A (en) |
| EP (1) | EP0277738B1 (en) |
| JP (1) | JPS63201184A (en) |
| KR (1) | KR900001422B1 (en) |
| CN (1) | CN1022324C (en) |
| AP (1) | AP52A (en) |
| AR (1) | AR243182A1 (en) |
| AT (1) | ATE73800T1 (en) |
| AU (1) | AU587736B2 (en) |
| BG (1) | BG51042A3 (en) |
| CA (1) | CA1335590C (en) |
| CS (2) | CS265250B2 (en) |
| CY (1) | CY1775A (en) |
| DD (1) | DD267490A5 (en) |
| DE (1) | DE3869149D1 (en) |
| DK (1) | DK44888A (en) |
| EC (1) | ECSP941082A (en) |
| ES (1) | ES2032955T3 (en) |
| FI (1) | FI89598C (en) |
| GR (1) | GR3004200T3 (en) |
| HK (1) | HK132695A (en) |
| IE (1) | IE60000B1 (en) |
| IL (1) | IL85277A (en) |
| IN (1) | IN171799B (en) |
| IS (1) | IS1533B (en) |
| LV (1) | LV10252B (en) |
| MA (1) | MA21171A1 (en) |
| MY (1) | MY102737A (en) |
| NO (1) | NO170581C (en) |
| NZ (1) | NZ223373A (en) |
| OA (1) | OA08710A (en) |
| PH (1) | PH26545A (en) |
| PL (1) | PL149550B1 (en) |
| PT (1) | PT86675B (en) |
| RO (1) | RO105052B1 (en) |
| RU (1) | RU2011381C1 (en) |
| SG (1) | SG27994G (en) |
| SI (1) | SI8810183A8 (en) |
| UA (1) | UA25898A1 (en) |
| WO (1) | WO1988005656A1 (en) |
| YU (1) | YU46766B (en) |
| ZA (1) | ZA88679B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4861794A (en) * | 1988-04-13 | 1989-08-29 | Pfizer Inc. | 3-substituted-2-oxindole-1-carboxamides as inhibitors of interleukin-1 biosynthesis |
| US4853409A (en) * | 1988-04-13 | 1989-08-01 | Pfizer Inc. | 3-substituted-2-oxindole-1-carboxamides for suppressing T-cell function |
| DE68923673T2 (en) * | 1988-10-18 | 1996-01-18 | Pfizer | Pro-drugs of anti-inflammatory 3-acyl-2-oxindole-1-carboxamides. |
| SK590689A3 (en) * | 1988-10-18 | 1996-03-06 | Pfizer | 3-aryl-2-oxindole-1-carboxamides and method of their preparation |
| US5059693A (en) * | 1989-10-06 | 1991-10-22 | Pfizer Inc. | Process for making 3-aroyl-2-oxindole-1-carboxamides |
| US5006547A (en) * | 1990-03-19 | 1991-04-09 | Pfizer Inc. | Tenidap as an inhibitor of the release of elastase by neutrophils |
| US5008283A (en) * | 1990-03-19 | 1991-04-16 | Pfizer Inc. | Use of tenidap to inhibit activation of collagenase and to inhibit the activity of myeloperoxidase |
| US5122534A (en) * | 1991-02-08 | 1992-06-16 | Pfizer Inc. | Use of tenidap to reduce total serum cholesterol, ldl cholesterol and triglycerides |
| DE4111305C2 (en) * | 1991-04-08 | 1994-12-01 | Mack Chem Pharm | Pharmaceutical preparation for rectal administration, which contains a 2-oxindole-1-carboxamide derivative |
| WO1997022605A1 (en) * | 1995-12-19 | 1997-06-26 | Pfizer Inc. | Stable, long acting salts of indole derivatives for the treatment of joint diseases |
| EP0826685A1 (en) * | 1996-08-21 | 1998-03-04 | Pfizer Inc. | Stable, long acting salts of carboxamides for the treatment of joint disease |
| DE19854355A1 (en) * | 1998-11-25 | 2000-05-31 | Bayer Ag | Crystal modification B of 8-cyan-1-cyclopropyl-7- (1S, 6S-2,8-diazabicyclo- / 4.3.O / nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo 3-quinoline carboxylic acid |
| US7407195B2 (en) | 2004-04-14 | 2008-08-05 | William Berson | Label for receiving indicia having variable spectral emissivity values |
| US7651031B2 (en) | 2004-10-25 | 2010-01-26 | William Berson | Systems and methods for reading indicium |
| US7728726B2 (en) * | 2005-01-14 | 2010-06-01 | William Berson | Radio frequency identification labels |
| US7931413B2 (en) * | 2005-01-14 | 2011-04-26 | William Berson | Printing system ribbon including print transferable circuitry and elements |
| US7619520B2 (en) * | 2005-01-14 | 2009-11-17 | William Berson | Radio frequency identification labels and systems and methods for making the same |
| US7621451B2 (en) * | 2005-01-14 | 2009-11-24 | William Berson | Radio frequency identification labels and systems and methods for making the same |
| KR20200085285A (en) | 2017-11-02 | 2020-07-14 | 애커러트 메디컬 테라퓨틱스 엘티디. | Embolization catheter with built-in filter |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3767653A (en) * | 1971-06-28 | 1973-10-23 | Squibb & Sons Inc | Thiazines |
| GB1532413A (en) * | 1974-12-23 | 1978-11-15 | Union International Co Ltd | Chenodeoxycholic acid |
| DE2613346C3 (en) * | 1976-03-29 | 1981-07-23 | Diamalt AG, 8000 München | Monocline crystalline chenodeoxycholic acid and process for its preparation |
| ATE63543T1 (en) * | 1984-02-07 | 1991-06-15 | Pfizer | 2-OXINDOLE INTERMEDIATE. |
| US4556672A (en) * | 1984-03-19 | 1985-12-03 | Pfizer Inc. | 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents |
| DE3579716D1 (en) * | 1984-03-19 | 1990-10-25 | Pfizer | METHOD FOR PRODUCING 2-OXINDOLE-1-CARBOXAMIDES AND THEIR INTERMEDIATE PRODUCTS. |
| US4569942A (en) * | 1984-05-04 | 1986-02-11 | Pfizer Inc. | N,3-Disubstituted 2-oxindole-1-carboxamides as analgesic and antiinflammatory agents |
-
1987
- 1987-02-02 RO RO140907A patent/RO105052B1/en unknown
- 1987-02-02 WO PCT/US1987/000201 patent/WO1988005656A1/en active IP Right Grant
- 1987-02-02 US US07/460,137 patent/US5036099A/en not_active Expired - Lifetime
- 1987-02-02 UA UA4614718A patent/UA25898A1/en unknown
-
1988
- 1988-01-25 ES ES88300561T patent/ES2032955T3/en not_active Expired - Lifetime
- 1988-01-25 AT AT88300561T patent/ATE73800T1/en not_active IP Right Cessation
- 1988-01-25 EP EP88300561A patent/EP0277738B1/en not_active Expired - Lifetime
- 1988-01-25 DE DE8888300561T patent/DE3869149D1/en not_active Expired - Fee Related
- 1988-01-27 IN IN67/DEL/88A patent/IN171799B/en unknown
- 1988-01-28 AP APAP/P/1988/000081A patent/AP52A/en active
- 1988-01-29 CA CA000557662A patent/CA1335590C/en not_active Expired - Fee Related
- 1988-01-29 DK DK044888A patent/DK44888A/en not_active Application Discontinuation
- 1988-02-01 NZ NZ223373A patent/NZ223373A/en unknown
- 1988-02-01 OA OA59273A patent/OA08710A/en unknown
- 1988-02-01 KR KR1019880000876A patent/KR900001422B1/en not_active IP Right Cessation
- 1988-02-01 BG BG082816A patent/BG51042A3/en unknown
- 1988-02-01 MA MA21408A patent/MA21171A1/en unknown
- 1988-02-01 AR AR88309983A patent/AR243182A1/en active
- 1988-02-01 PT PT86675A patent/PT86675B/en not_active IP Right Cessation
- 1988-02-01 PL PL1988270415A patent/PL149550B1/en unknown
- 1988-02-01 SI SI8810183A patent/SI8810183A8/en not_active IP Right Cessation
- 1988-02-01 YU YU18388A patent/YU46766B/en unknown
- 1988-02-01 DD DD88312599A patent/DD267490A5/en not_active IP Right Cessation
- 1988-02-01 IL IL8527788A patent/IL85277A/en not_active IP Right Cessation
- 1988-02-01 ZA ZA88679A patent/ZA88679B/en unknown
- 1988-02-01 AU AU11160/88A patent/AU587736B2/en not_active Ceased
- 1988-02-01 PH PH36441A patent/PH26545A/en unknown
- 1988-02-02 JP JP63022675A patent/JPS63201184A/en active Granted
- 1988-02-02 CS CS88648A patent/CS265250B2/en unknown
- 1988-02-02 MY MYPI88000091A patent/MY102737A/en unknown
- 1988-02-02 IS IS3309A patent/IS1533B/en unknown
- 1988-02-02 CN CN88100555A patent/CN1022324C/en not_active Expired - Fee Related
- 1988-09-29 NO NO88884329A patent/NO170581C/en not_active IP Right Cessation
-
1989
- 1989-07-18 IE IE26988A patent/IE60000B1/en not_active IP Right Cessation
- 1989-08-01 FI FI893647A patent/FI89598C/en not_active IP Right Cessation
- 1989-08-01 RU SU894614718A patent/RU2011381C1/en not_active IP Right Cessation
-
1991
- 1991-11-22 CS CS913541A patent/CS354191A3/en unknown
-
1992
- 1992-03-31 GR GR920400571T patent/GR3004200T3/el unknown
-
1993
- 1993-11-15 LV LVP-93-1225A patent/LV10252B/en unknown
-
1994
- 1994-02-22 SG SG27994A patent/SG27994G/en unknown
- 1994-05-05 EC EC1994001082A patent/ECSP941082A/en unknown
-
1995
- 1995-08-24 HK HK132695A patent/HK132695A/en not_active IP Right Cessation
-
1996
- 1996-04-05 CY CY177596A patent/CY1775A/en unknown
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